The present invention relates to a method for treatment of external secretion disorders, particularly, to a method for treatment of hypolacrimation including dry-eye syndrome and hyposalivation including dry-mouth syndrome.
External secretions are discharges that are discharged directly from the exocrine glandular cells or through the excretory ducts or the like onto the body surface or into a lumen. Tear and saliva are the typical external secretions and secretions from the nasal or the respiratory tract mucosa, secretions from the stomach or the intestine, discharges from the vagina, perspiration, etc are also included. Conditions resulting from external secretion disorders include dryness of various parts of the body such as xe2x80x9cdry-eye syndromexe2x80x9d (xerophthalmia), xe2x80x9cdry-mouth syndromexe2x80x9d (xerostomia), xe2x80x9cdry nose syndromexe2x80x9d (xeromycteria), xe2x80x9cdry-skin syndromexe2x80x9d (xeroderma), and xe2x80x9cdry-vagina syndromexe2x80x9d (symptom of vaginal dryness); and chronic pancreatitis, chronic gastritis, and chronic bronchitis due to depression of the external secretion.
xe2x80x9cSjxc3x6gren""s syndromexe2x80x9d, an autoimmune disease, is one of the variety of known and unknown etiologic factors which may responsible for external secretion disorders. Sjxc3x6gren""s syndrome is characterized by dryness condition due to infiltration of inflammatory cells into the acinus of the exocrine gland and around the excretory duct, which results in destruction and atrophy of the acinus and the epithelial cells of the duct. Typical symptoms include eye and mouth dryness, as well as dryness of skin, nose, throat, bronchia, vulva, and vagina. For example, dryness of the respiratory tract may induce infections in the lung and sometimes may cause serious disorders such as pneumonia that may lead to death. The other major etiology is aging. Although the external secretion disorders may cause serious diseases as mentioned above, merely symptomatic treatment methods such as artificial hydration have been available for the disorders so far. Therefore, development of a fundamental treatment to improve the depressed external secretion has been desired.
One of the diseases caused by the external secretion disorders, and which has been a current keen interest in the medical and pharmaceutical field, is hypolacrimation including dry-eye syndrome.
Dry-eye syndrome is defined as a condition with decrease or change in quality of tear irrespective of the presence or absence of corneal and conjunctival lesion (Yamada et al., GANKI 43, 1289-1293(1992)). It include dry-eye conditions found in the patients of hypolacrimation, alacrima, xerophthalmia, Sjxc3x6gren""s syndrome, keratoconjunctivitis sicca, Stevens-Johnson syndrome, ocular pemphigoid, blepharitis marginal, and diabetes, etc.; post-cataract surgery dry eye; allergic conjunctivitis-associated dry eye; and age-related dry-eye syndrome. Further, dry-eye also includes the conditions found in hypolacrimation patients induced by long time visual display terminal (VDT) operations, room dryness due to air-conditioning and the like.
There are various etiologies of the dry-eye syndrome, including the above described and that have unidentified. However, at present, only palliative treatments for the dry-eye syndrome including administering an artificial tear solution to increase the quantity of tear retained within the conjunctival sac thereby relieve the subjective symptoms or protecting the eyes from dryness have been available. It has been desired to provide compositions which is capable of bringing satisfactory treatment, including improvement of hypolacrimation.
The tear secretion is classified into basal tear secretion and reflex tear secretion. Basal tear secretion is that under ordinary conditions with the eyelid open, and is considered being mainly from the accessory lacrimal glands e.g. Kraus gland and Wolfring gland. On the other hand, reflux tear secretion is tear secretion in response to some stimulation in the keratoconjunctival surface, nasal mucosa, or the like, or that accompanied with mental changes such as grief or joy. It is considered to be from the main lacrimal gland. Considering the symptoms of the dry-eye syndrome, improvement of the decreased basal tear secretion, i.e. tear secretion under ordinary conditions with the eyelid open, is particularly important.
Further, the diseases caused by external secretion disorders also include hyposalivation, and it may be sometimes accompanied by dry-mouth syndrome (xerostomia). In dry-mouth patients, the decreased amount of saliva secretion causes dryness of the lip and oral cavity and may induce thirst feeling, xerosis of tunica mucosa oris, urtication, dysmaesesis, and dyspepsia. Also, in the patients with dry-mouth syndrome, foods are likely to remain inside the mouth and may result in dental caries.
There are a variety of etiologic factors which are responsible for the dry-mouth syndrome. For example, systemic factors include febrile disease, dehydration, endocrinopathy (myxedema, Basedow""s disease, diabetes insipidus, etc.) metabolic disorders (diabetes, uremia, liver cirrhosis, etc.) deficiency of Vitamin-A, B, autoimmune disease (Sjxc3x6gren""s syndrome, progressive scleroderma, etc.) anemia, bleeding, aging, various medicaments (sedatives, parasympatholytic drugs, antihistamines, etc.). Local factors include sialadenitis, atrophy of salivary gland, sequela of radio therapy, and malformation (ectodermal dysplasia, etc.)
As described above, there are a variety of known and unknown etiologic factors responsible for the dry-mouth syndrome. However, at present, only palliative treatments for the dry-mouth syndrome such as drinking liquid all day long little by little, chewing gum or the like, and using artificial saliva have been available. It has been desired to provide a composition which is capable of bringing fundamental treatment such that to improve the decreased saliva secretion.
Generally, a healthy normal person discharges 1 to 1.5 litter of saliva a day through a pair of left and right major salivary glands (including parotid gland, submandibular gland, and sublingual gland) and minor salivary glands (including labial glands, lingual glands, palatine glands, and buccal glands). Saliva is discharged in response to a stimulant which may harm body to dilute the same or to maintain the physiological pH value, as well as helping mastication and deglutition of foods. Further, saliva dissolves foods thereby makes a person taste them and helps him smoothly utter words by keeping a wet state inside the mouth. There are two types of saliva: one is the continuous type that keeps on discharging a small amount without a particular stimulant and the other is the reflective type that is discharged in response to stimulation by food, gnatho-movement, taste and the like. In any case, saliva secretion is one of the essential physiological functions and hence improving the decreased saliva secretion is particularly important in treating the dry-mouth syndrome.
In the past, some of fatty acids had been rated as essential, and enough amount of them were required to be taken from the nutrient point of view. Recently, bioactivities of a variety of fatty acids have been studied and the activities of linoleic acid, arachidonic acid, xcex1-linolenic acid, eicosapentaenoic acid (EPA), and docosahexaenoic acid (DHA) have attracted the attention. linoleic acid is converted through di-homo-xcex3-linolenic acid to arachidonic acid; xcex1-linolenic acid is converted through eicosapentaenoic acid (EPA) to docosahexaenoic acid (DHA); di-homo-xcex3-linolenic acid is converted into type 1 prostaglandin (PG1), arachidonic acid is converted into type 2 prostaglandin (PG2) or type 4 leukotriene (LT4), and eicosapentaenoic acid is converted into type 3 prostaglandin or type 5 leukotriene (LT5) in vivo respectively.
Prostaglandins (hereinafter, referred to as PG(s)) are members of class of organic carboxylic acids, which are contained in tissues or organs of human or most other mammalian, and exhibit a wide range of physiological activity. PGs found in nature (primary PGs) generally have a prostanoic acid skeleton as shown in the formula (A): 
On the other hand, some of synthetic analogues have a modified skeleton. The primary PGs are classified to PGAs, PGBs, PGCs, PGDs, PGEs, PGFs, PGGs, PGHs, PGIs and PGJs according to the structure of the five-membered ring moiety, and further classified into the following three types by the number and position of the unsaturated bond at the carbon chain moiety:
subscript 1: 13,14-unsaturated-15-OH
subscript 2: 5,6- and 13,14-diunsaturated-15-OH
subscript 3: 5,6-, 13,14-, and 17,18-triunsaturated-15-OH.
Further, the PGFs are classified, according to the configuration of the hydroxyl group at the 9-position, into xcex1 type (the hydroxyl group is of an xcex1-configuration) and xcex2 type (the hydroxyl group is of a xcex2-configuration).
In addition, some 15-keto (i.e. having an oxo group at position 15 in place of the hydroxy group) prostaglandins and 13,14-dihydro-15-keto-prostaglandins are known as substances naturally produced by enzymatic actions during in vivo metabolism of primary PGs. 15-keto PGs have been disclosed in, for example, EP-A-0281239 (corresponds to JP-A-104040/89), EP-A-0281480 (corresponds to JP-A-52753/89), EP-A-0289349 (corresponds to JP-A-151552/89), EP-A-0453127 (JP-A-58992/95) and EP-A-0690049 (corresponds to JP-A-48665/96). These cited references are herein incorporated by reference.
For example, when a primary type PG such as PGE2 or PGF2xcex1 which is a fatty acid derivative is instilled to the eyes at a stimulating amount which induces conjunctival hyperemia, lacrimation will occur simultaneously with the hyperemia. However, at an amount as low as that does not induce any conjunctival hyperemia, it is not known about the effect of the fatty acid derivatives including PGs on the tear secretion, basal tear secretion which is not affected by a stimulant, nor saliva secretion.
An object of the present invention is to provide a method for treatment of external secretion disorders, especially the method useful for treatment of at least one condition selected from hypolacrimation, dry-eye syndrome, hyposalivation and dry-mouth syndrome.
The present inventor found that at an amount as low as that does not induce any conjunctival hyperemia, a fatty acid derivative may improve hypolacrimation, improve basal tear secretion which is not affected by a stimulant, and improve the dry-eye conditions. In addition, the inventor also found that the fatty acid derivative might also improve hyposalivation, and improve dry-mouth conditions.
Therefore, the present invention provides a method for treatment of external secretion disorders, especially, for treatment of hypolacrimation, dry-eye syndrome, hyposalivation or dry-mouth syndrome, which comprises administering an effective amount of a fatty acid derivative to a subject in need of said treatment.
According to this invention, the term xe2x80x9cfatty acidxe2x80x9d includes not only the above mentioned linoleic acid, di-homo-xcex3-linolenic acid, arachidonic acid, xcex1-linolenic acid, eicosapentaenoic acid (EPA) and docosahexaenoic acid (DHA), but also a compound comprising at least one carboxylic acid moiety irrespective to presence or absence of double bonds, a cyclic group or a substitute group, the number of the carbon atoms, position or number of the double bonds, or a modification on the chain. In addition, the fatty acid derivatives include not only the fatty acids as above but also prostaglandin like compounds which include PGS derived from said fatty acids, leukotriene like compounds, thromboxanes, hydroxyeicosatetraenoic acids, hydroperoxyeicosatetraenoic acids or their derivatives.
Furthermore, in the present invention, the fatty acid derivatives also include the compound which have at least xe2x80x94COOH or xe2x80x94CH2OH or the functional derivatives (salts, esters, ethers, amides or the like) thereof at the terminal carbon atom, irrespective to presence or absence of double bonds, a cyclic group or a substitute group, the number of the carbon atoms, position or number of the double bonds, or a modification on the chain.
According to the present invention, the term xe2x80x9cprostaglandin like compoundxe2x80x9d (hereinafter, referred as xe2x80x9cPG like compoundxe2x80x9d) includes any of derivatives or substituted derivatives of a compound having the prostanoic acid basic structure irrespective to the configuration of the 5-memberd ring, number of double bonds in the xcex1 or xcfx89 chain, presence or absence of hydroxy and oxo groups or any other substituent, or any other modification. Since the PG like compound of the present invention may have an activity as an agonist for PG-receptor such as EP, FP, IP TP or DP receptor, the xe2x80x9cPG like compoundxe2x80x9d of the present invention may include each compound having PG-receptor agonistic activity irrespective to their structure.
The nomenclature of the PG like compounds used herein is based on the numbering system of the prostanoic acid represented in the above formula (A).
The formula (A) shows a basic skeleton of the C-20, but the PG like compounds in the present invention are not limited to those having the same number of carbon atoms. In the formula (A), the numbering of the carbon atoms which constitute the basic skeleton of the PG compounds starts at the carboxylic acid (numbered 1), and carbon atoms in the xcex1-chain are numbered 2 to 7 towards the five-membered ring, those in the ring are 8 to 12, and those in the xcfx89-chain are 13 to 20. When the number of carbon atoms is decreased in the xcex1-chain, the number is deleted in the order starting from position 2; and when the number of carbon atoms is increased in the xcex1-chain, compounds are named as substitution compounds having respective substituents at position 2 in place of carboxy group (C-1). Similarly, when the number of carbon atoms is decreased in the xcfx89-chain, the number is deleted in the order starting from position 20; and when the number of carbon atoms is increased in the xcfx89-chain, the carbon atoms over position 20 are named as substituents. Stereochemistry of the compounds is the same as that of the above formula (A) unless otherwise specified.
In general, each of PGD, PGE and PGF represents a PG compound having hydroxy groups at positions 9 and/or 11, but in the present specification, they also include those having substituents other than the hydroxy group at positions 9 and/or 11. Such compounds are referred to as 9-dehydroxy-9-substituted-PG compounds or 11-dehydroxy-11-substituted-PG compounds. A PG compound having hydrogen in place of the hydroxy group is simply named as 9- or 11-dehydroxy compound.
As stated above, the nomenclature of the PG like compounds is based on the prostanoic acid skeleton. However, in case the compound has a similar partial construction as a prostaglandin, the abbreviation of xe2x80x9cPGxe2x80x9d may be used. Thus, a PG compound of which xcex1-chain is extended by two carbon atoms; that is, having 9 carbon atoms in the xcex1-chain is named as 2-decarboxy-2-(2-carboxyethyl)-PG compound. Similarly, a PG compound having 11 carbon atoms in the xcex1-chain is named as 2-decarboxy-2-(4-carboxybutyl)-PG compound, and a PG compound having 10 carbon atoms in the xcfx89-chain is named as 20-ethyl-PG compound. These compounds, however, may also be named according to the IUPAC nomenclatures.
The PG like compounds used in the present invention may include any of PG derivatives. Accordingly, for example, a PG1 compound having a double bond at 13-14 position and a hydroxy group at 15-position, a PG2 compound having another double bond at 5-6 position, a PG3 compound having further double bond at 17-18 position, a 15-keto-PG compound having an oxo group in place of the hydroxy group at the 15-position, a 15-dehydroxy-PG compound having a hydrogen atom in place of the hydroxy group at the 15-position, or either 13,14-dihydro-PG compound wherein the double bond at 13-14 position is single bond, or 13,14-didehydro-PG compound wherein the double bond at the 13-14-position is triple bond. Moreover, examples of substituted compounds and derivatives include a compound wherein the terminal carboxyl group in the xcex1-chain of the above described compound is esterified, a physiologically acceptable salt thereof, a compound wherein the number of carbon atoms in the xcex1- or xcfx89-chain is decreased or increased, a compound having side chains (e.g., 1 to 3 carbon atoms) on xcex1- or xcfx89-chains, a compound having substituent(s) such as hydroxy, halogen, lower alkyl, hydroxy(lower)alkyl, and oxo, or double bond(s) on the five-membered ring, a compound having substituent(s), such as halogen, oxo, aryl and heterocyclic on the xcex1-chain, a compound having substituents such as halogen, oxo, hydroxy, lower alkoxy, lower alkanoyloxy, cyclo(lower)alkyl, cyclo(lower)alkyloxy, aryl, aryloxy, heterocyclic and heterocyclic-oxy on the xcfx89-chain, and a compound having substituent such as lower alkoxy, lower alkanoyloxy, cyclo(lower)alkyl, cyclo(lower)alkyloxy, aryl, aryloxy, heterocyclic and heterocyclic-oxy at the terminal of the xcfx89-chain of which is shorter than that of normal prostanoic acid.
A preferred compound used in the present invention is represented by the formula (I): 
wherein
W1, W2 and W3 are carbon or oxygen atoms,
L, M and N are hydrogen, hydroxy, halogen, lower alkyl, hydroxy(lower)alkyl, or oxo, wherein at least one of L and M is a group other than hydrogen, and the five-membered ring may have at least one double bond;
A is xe2x80x94CH2OH, xe2x80x94COCH2OH, xe2x80x94COOH or its functional derivative;
B is single bond, xe2x80x94CH2xe2x80x94CH2xe2x80x94, xe2x80x94CHxe2x95x90CHxe2x80x94, xe2x80x94Cxe2x89xa1Cxe2x80x94, xe2x80x94Ch2xe2x80x94CH2xe2x80x94CH2xe2x80x94, xe2x80x94CHxe2x95x90CHxe2x80x94CH2xe2x80x94, xe2x80x94CH2xe2x80x94CHxe2x95x90CHxe2x80x94, xe2x80x94Cxe2x89xa1Cxe2x80x94CH2xe2x80x94, or xe2x80x94CH2xe2x80x94Cxe2x89xa1Cxe2x80x94;
Z is 
wherein R4 and R5 are hydrogen, hydroxy, halogen, lower alkyl, lower alkoxy or hydroxy(lower)alkyl, wherein R4 and R5 are not hydroxy and lower alkoxy at the same time;
R1 is a divalent saturated or unsaturated lower-medium aliphatic hydrocarbon residue, which is unsubstituted or substituted by halogen, oxo, hydroxy, lower alkyl, aryl or heterocyclic; and
Ra is a saturated or unsaturated lower-medium aliphatic hydrocarbon residue, which is unsubstituted or substituted by halogen, oxo, lower alkyl, hydroxy, lower alkoxy, lower alkanoyloxy, cyclo(lower)alkyl, cyclo(lower)alkyloxy, aryl, aryloxy, heterocyclic or heterocyclic-oxy; cyclo(lower)alkyl; cyclo(lower)alkyloxy; aryl; aryloxy; heterocyclic; heterocyclic-oxy.
A group of particularly preferable compounds among the above described compounds is represented by the general formula (II): 
wherein
L and M are hydrogen, hydroxy, halogen, lower alkyl, hydroxy(lower)alkyl, or oxo, wherein at least one of L and M is a group other than hydrogen, and the five-membered ring may have at least one double bond;
A is xe2x80x94CH2OH, xe2x80x94COCH2OH, xe2x80x94COOH or its functional derivative;
B is single bond, xe2x80x94CH2xe2x80x94CH2xe2x80x94, xe2x80x94CHxe2x95x90CHxe2x80x94, xe2x80x94Cxe2x89xa1Cxe2x80x94, xe2x80x94CH2xe2x80x94CH2xe2x80x94CH2xe2x80x94, xe2x80x94CHxe2x95x90CHxe2x80x94CH2xe2x80x94, xe2x80x94CH2xe2x80x94CHxe2x95x90CHxe2x80x94, xe2x80x94Cxe2x89xa1Cxe2x80x94CH2xe2x80x94, or xe2x80x94CH2xe2x80x94Cxe2x89xa1Cxe2x80x94;
Z is 
wherein R4 and R5 are hydrogen, hydroxy, halogen, lower alkyl, lower alkoxy or hydroxy(lower)alkyl, wherein R4 and R5 are not hydroxy and lower alkoxy at the same time;
X1 and X2 are hydrogen, lower alkyl, or halogen;
R1 is a divalent saturated or unsaturated lower-medium aliphatic hydrocarbon residue, which is unsubstituted or substituted by halogen, oxo, hydroxy, lower alkyl, aryl or heterocyclic;
R2 is a single bond or lower alkylene; and
R3 is lower alkyl, lower alkoxy, cyclo(lower)alkyl, cyclo(lower)alkyloxy, aryl, aryloxy, heterocyclic or heterocyclic-oxy.
Other preferred compound used in the present invention is represented by the formula (III): 
wherein
Q1 and Q2 are hydrogen or lower alkyl, or Q1 and Q2 are linked together to form xe2x80x94(CH2)nxe2x80x94 wherein n is 1, 2 or 0, and six-membered ring may have at least one double bond;
A is xe2x80x94CH2OH, xe2x80x94COCH2OH, xe2x80x94COOH or its functional derivative;
B is single bond, xe2x80x94CH2xe2x80x94CH2xe2x80x94, xe2x80x94CHxe2x95x90CHxe2x80x94, xe2x80x94Cxe2x89xa1Cxe2x80x94, xe2x80x94CH2xe2x80x94CH2xe2x80x94CH2xe2x80x94, xe2x80x94CHxe2x95x90CHxe2x80x94CH2xe2x80x94, xe2x80x94CH2xe2x80x94CHxe2x95x90CHxe2x80x94, xe2x80x94Cxe2x89xa1Cxe2x80x94CH2xe2x80x94, or xe2x80x94CH2xe2x80x94Cxe2x89xa1Cxe2x80x94;
Z is 
wherein R4 and R5 are hydrogen, hydroxy, halogen, lower alkyl, lower alkoxy or hydroxy(lower)alkyl, wherein R4 and R5 are not hydroxy and lower alkoxy at the same time;
R1 is a divalent saturated or unsaturated lower-medium aliphatic hydrocarbon residue, which is unsubstituted or substituted by halogen, oxo, hydroxy, lower alkyl, aryl or heterocyclic;
Ra is a saturated or unsaturated lower-medium aliphatic hydrocarbon residue, which is unsubstituted or substituted by halogen, oxo, hydroxy, alkyl, lower alkoxy, lower alkanoyloxy, cyclo(lower)alkyl, cyclo(lower)alkyloxy, aryl, aryloxy, heterocyclic or heterocyclic-oxy; cyclo(lower)alkyl; cyclo(lower)alkyloxy; aryl; aryloxy; heterocyclic; heterocyclic-oxy; and
the six-memberd ring may optionally have one or more double bonds and may optionally consist a conjugated system.
Among the above described compound (III), a preferable compound is benzene ring type compound in the six-membered ring.
In the above formula, the term xe2x80x9cunsaturatedxe2x80x9d in the definitions for R1 and Ra is intended to include at least one or more double bonds and/or triple bonds that are isolatedly, separately or serially present between carbon atoms of the main and/or side chains. According to the usual nomenclature, an unsaturated bond between two serial positions is represented by denoting the lower number of the two positions, and an unsaturated bond between two distal positions is represented by denoting both of the positions. Preferred unsaturated bonds are a double bond at position 2 and a double or triple bond at position 5.
The term xe2x80x9clower-medium aliphatic hydrocarbonxe2x80x9d means a hydrocarbon having a straight or branched chain of 1 to 14 carbon atoms, wherein the side chain has preferably 1 to 3 carbon atoms. The preferred R1 has 1 to 10, more preferably, 1 to 8 carbon atoms, and the preferred Ra has 1 to 10, more preferably, 1 to 8 carbon atoms.
The term xe2x80x9chalogenxe2x80x9d includes fluorine, chlorine, bromine, and iodine.
The term xe2x80x9clowerxe2x80x9d means a group having 1 to 6 carbon atoms unless otherwise specified.
The term xe2x80x9clower alkylxe2x80x9d means a straight- or branched-chain saturated hydrocarbon group having 1 to 6 carbon atoms, for example, methyl, ethyl, propyl, isopropyl, butyl, isobutyl, t-butyl, pentyl, and hexyl.
The term xe2x80x9clower alkoxyxe2x80x9d means a lower alkyl-Oxe2x80x94 wherein the lower alkyl is as described above.
The term xe2x80x9chydroxy(lower)alkylxe2x80x9d means an alkyl as described above, which is substituted by at least one hydroxy group, for example, hydroxymethyl, 1-hydroxyethyl, 2-hydroxyethyl, and 1-methyl-1-hydroxyethyl.
The term xe2x80x9clower alkanoyloxyxe2x80x9d means a group represented by the formula RCOxe2x80x94Oxe2x80x94, wherein RCOxe2x80x94 is an acyl formed by oxidation of a lower alkyl as described above, for example, acetyl.
The term xe2x80x9clower cycloalkylxe2x80x9d means a group formed by cyclization of a lower alkyl group containing 3 or more carbon atoms as described above, for example, cyclopropyl, cyclobutyl, cyclopentyl, and cyclohexyl.
The term xe2x80x9ccyclo(lower)alkyloxyxe2x80x9d means a group represented by the formula cycloalkyl-Oxe2x80x94, wherein cycloalkyl is described above.
The term xe2x80x9carylxe2x80x9d includes aromatic hydrocarbon rings (preferably monocyclic groups) which may be substituted, for example, phenyl, tolyl and xylyl. Examples of the substituent in this case include halogen, and halogen substituted lower alkyl group, wherein halogen atom and lower alkyl group are as described above.
The term xe2x80x9caryloxyxe2x80x9d means a group represented by the formula ArOxe2x80x94, wherein Ar is an aryl group as described above.
The term xe2x80x9cheterocyclicxe2x80x9d includes mono- to tricyclic, preferably monocyclic heterocyclic group which is 5 to 14, preferably 5 to 10 membered ring having optionally substituted carbon atom and 1 to 4, preferably 1 to 3 of 1 or 2 type of hetero atoms selected from nitrogen atom, oxygen atom and sulfur atom. Examples of the heterocyclic group include furyl, thienyl, pyrrolyl, oxazolyl, isoxazolyl, thiazolyl, isothiazolyl, imidazolyl, pyrazolyl, furazanyl, pyranyl, pyridyl, pyridazyl, pyrimidyl, pyrazyl, 2-pyrrolinyl, pyrrolidinyl, 2-imidazolinyl, imidazolidinyl, 2-pyrazolinyl, pyrazolidinyl, piperidino, piperazinyl, morpholino, indolyl, benzothienyl, quinolyl, isoquinolyl, puryl, quinazolinyl, carbazolyl, acridinyl, phenanthridinyl, benzimidazolyl, benzimidazolonyl, benzothiazolyl, phenothiazinyl. Examples of the substituent in this case include halogen, and halogen substituted lower alkyl group, wherein halogen atom and lower alkyl group are as described above.
The term xe2x80x9cheterocyclic-oxyxe2x80x9d means a group represented by the formula HcOxe2x80x94, wherein Hc is a heterocyclic group as described above.
The term xe2x80x9cfunctional derivativexe2x80x9d of A includes salts (preferably pharmaceutically acceptable salts), ethers, esters, and amides.
Examples of suitable xe2x80x9cpharmaceutically acceptable saltsxe2x80x9d include nontoxic salts which are commonly used, and salts with inorganic bases, for example, alkali metal salts (sodium salt, potassium salt and the like); alkaline earth metal salts (calcium salt, magnesium salt and the like); ammonium salts; salts with organic bases, for example, amine salts (such as methylamine salt, dimethylamine salt, cyclohexylamine salt, benzylamine salt, piperidine salt, ethylenediamine salt, ethanolamine salt, diethanolamine salt, triethanolamine salt, tris(hydroxymethylamino)ethane salt, monomethyl-monoethanolamine salt, lysine salt, procaine salt, and caffeine salt); basic amino acid salts (such as arginine salt, and lysine salt); tetraalkyl ammonium salts and the like. These salts may be manufactured from, for example, corresponding acids and bases in accordance with a conventional manner or salt exchange.
Examples of the ethers include alkyl ethers, for example, lower alkyl ethers such as methyl ether, ethyl ether, propyl ether, isopropyl ether, butyl ether, isobutyl ether, t-butyl ether, pentyl ether and 1-cyclopropyl ethyl ether; and medium or higher alkyl ethers such as octyl ether, diethylhexyl ether, lauryl ether and cetyl ether; unsaturated ethers such as oleyl ether and linolenyl ether; lower alkenyl ethers such as vinyl ether, allyl ether; lower alkynyl ethers such as ethynyl ether and propynyl ether; hydroxy(lower)alkyl ethers such as hydroxyethyl ether and hydroxyisopropyl ether; lower alkoxy(lower)alkyl ethers such as methoxymethyl ether and 1-methoxyethyl ether; optionally substituted aryl ethers such as phenyl ether, tosyl ether, t-butylphenyl ether, salicyl ether, 3,4-di-methoxyphenyl ether and benzamidophenyl ether; and aryl(lower)alkyl ethers such as benzyl ether, trityl ether and benzhydryl ether.
Examples of the esters include aliphatic esters, for example, lower alkyl esters such as methyl ester, ethyl ester, propyl ester, isopropyl ester, butyl ester, isobutyl ester, t-butyl ester, pentyl ester, and 1-cyclopropylethyl ester; lower alkenyl esters such as vinyl ester, and allyl ester; lower alkynyl esters such as ethynyl ester, and propynyl ester; hydroxy(lower)alkyl esters such as hydroxyethyl ester; and lower alkoxy(lower)alkyl esters such as methoxymethyl ester, and 1-methoxyethyl ester as well as, for example, optionally substituted aryl esters such as phenyl ester, tosyl ester, t-butylphenyl ester, salicyl ester, 3,4-dimethoxyphenyl ester, and benzamidephenyl ester; and aryl(lower)alkyl esters such as benzyl ester, trityl ester, and benzhydryl ester. An example of amides includes mono- or di-lower alkyl amides such as methylamide, ethylamide, and dimethylamide; aryl amides such as anilide, and toluidide; and alkyl or aryl sulfonyl amides such as methylsulfonyl amide, ethylsulfonyl amide, and tolylsulfonyl amide.
Preferred examples of L and M include hydroxy and oxo, and especially, M is hydroxy and L is oxo which provide a 5-membered ring structure of, so called, PGE type.
Preferred examples of A-group include xe2x80x94COOH, and a pharmaceutically acceptable salt, an ester and an amide thereof.
In the formula (I) and (II), B is preferably xe2x80x94CH2xe2x80x94CH2xe2x80x94 which provides the structure of so-called, 13,14-dihydro type.
In the formula (III), B is preferably single bond.
In the formula (I) and (II), Z is preferably =O which provides the structure of so-called keto-type.
In the formula (III), Z is preferably hydroxy.
Preferred examples of X1 and X2 are that at least one of them is halogen, more preferably, both of them are halogen, especially, fluorine that provides a structure of, so called 16,16-difluoro type.
Preferred R1 is a hydrocarbon containing 2-10 carbon atoms, more preferably, 4-8 carbon atoms.
Examples of R1 include, for example, the following groups:
xe2x80x94CH2xe2x80x94CH2xe2x80x94CH2xe2x80x94CH2xe2x80x94,
xe2x80x94CH2xe2x80x94CHxe2x95x90CHxe2x80x94CH2xe2x80x94,
xe2x80x94CH2xe2x80x94Cxe2x89xa1Cxe2x80x94CH2xe2x80x94
xe2x80x94CH2xe2x80x94CH2xe2x80x94CH2xe2x80x94CH2xe2x80x94CH2xe2x80x94,
xe2x80x94CH2xe2x80x94CHxe2x95x90CHxe2x80x94CH2xe2x80x94CH2xe2x80x94,
xe2x80x94CH2xe2x80x94Cxe2x89xa1Cxe2x80x94CH2xe2x80x94CH2xe2x80x94
xe2x80x94CH2xe2x80x94CH2xe2x80x94CH2xe2x80x94CH2xe2x80x94CH2xe2x80x94CH2xe2x80x94,
xe2x80x94CH2xe2x80x94CHxe2x95x90CHxe2x80x94CH2xe2x80x94CH2xe2x80x94CH2xe2x80x94,
xe2x80x94CH2xe2x80x94CH2xe2x80x94CH2xe2x80x94CH2xe2x80x94CHxe2x95x90CHxe2x80x94
xe2x80x94CH2xe2x80x94Cxe2x89xa1Cxe2x80x94CH2xe2x80x94CH2xe2x80x94CH2xe2x80x94
xe2x80x94CH2xe2x80x94CH2xe2x80x94CH2xe2x80x94CH2xe2x80x94CH(CH3)xe2x80x94CH2xe2x80x94
xe2x80x94CH2xe2x80x94CH2xe2x80x94CH2xe2x80x94CH2xe2x80x94CH2xe2x80x94CH2xe2x80x94CH2xe2x80x94CH2xe2x80x94,
xe2x80x94CH2xe2x80x94CHxe2x95x90CHxe2x80x94CH2xe2x80x94CH2xe2x80x94CH2xe2x80x94CH2xe2x80x94CH2xe2x80x94,
xe2x80x94CH2xe2x80x94CH2xe2x80x94CH2xe2x80x94CH2xe2x80x94CH2xe2x80x94CH2xe2x80x94CHxe2x95x90CHxe2x80x94,
xe2x80x94CH2xe2x80x94Cxe2x89xa1Cxe2x80x94CH2xe2x80x94CH2xe2x80x94CH2xe2x80x94CH2xe2x80x94CH2xe2x80x94,
xe2x80x94CH2xe2x80x94CH2xe2x80x94CH2xe2x80x94CH2xe2x80x94CH2xe2x80x94CH2xe2x80x94CH(CH3)xe2x80x94CH2xe2x80x94,
Preferred Ra is a hydrocarbon containing 1-10 carbon atoms, more preferably, 1-8 carbon atoms and, especially, that having one or two side chains with one carbon atom.
The configuration of the ring and the xcex1- and/or xcfx89 chains in the above formula (I) may be the same as or different from that of the primary PGs. However, the present invention also includes a mixture of a compound having a primary type configuration and a compound of a non-primary type configuration.
An example of the typical compound according to the present invention is 13,14-dihydro-15-keto-16-mono or di-fluoro PGE compound or a derivative thereof.
When a 15-keto-PG compound of the present invention has a saturated bond between positions 13 and 14, the compound may be in the keto-hemiacetal equilibrium by formation of a hemiacetal between hydroxy at position 11 and keto at position 15.
If such tautomeric isomers as above are present, the proportion of both tautomeric isomers varies with the structure of the rest of the molecule or the kind of the substituent present. Sometimes one isomer may predominantly be present in comparison with the other. However, it is to be appreciated that the compounds used in the invention include both isomers. Further, while the compounds used in the invention may be represented by a structure formula or name based on keto-type regardless of the presence or absence of the isomers, it is to be noted that such structure or name does not intend to eliminate the hemiacetal type compound.
In the present invention, any of isomers such as the individual tautomeric isomers, the mixture thereof, or optical isomers, the mixture thereof, a racemic mixture, and other steric isomers may be used in the same purpose.
Some of the compounds used in the present invention may be prepared by the method disclosed in EP-A 0281239 (corresponding to JP-A 64-052753), EP-A 0284180 (corresponding to JP-A 01-104040), EP-A 0289349 (corresponding to JP-A 01-151519), EP-A 0453127 (corresponding to JP-A 05-58992), EP-A 0690049 (corresponding to JP-A 08-48665) or U.S. Pat. No. 5369127. The references as above are herein incorporated by reference. Alternatively, these compounds may be prepared by a process analogous to that described herein or by any process known in the art.
As mentioned above, one of the characteristics of the PG like compounds of the present invention is a PG-receptor (ex. EP, FP, IP, TP and DP-receptor) agonist activity. Accordingly, the PG like compounds used in the present invention include any of compounds having a PG-receptor agonist activity, irrespective to their structure.
The above described fatty acid derivatives of the present invention are effective in treating external secretion disorders, especially in treating hypolacrimation including disorders in basal tear secretion, as well as in improving and treating of dry-eye conditions (i.e. decreased lacrimal fluid secretion and accompanying corneal disorders). Further, said compounds are also effective in improving hyposalivation, as well as in improving and treating of dry-mouth conditions. Therefore, the composition is useful for treatment of external secretion disorders, especially hypolacrimation including disorders in basal tear secretion and/or dry eye condition, or hyposalivation and/or dry-mouth conditions.
The term xe2x80x9ctreatmentxe2x80x9d or xe2x80x9ctreatingxe2x80x9d used herein refers to any means of control of a condition of a subject including prevention, cure, relief of the condition, and arrestation or relief of development of the condition.
The subjects who are intended to be treated by the method of the present invention are those suffered from external secretion disorder including xerosises such as dry-eye syndrome (xerophthalmia), dry-mouth syndrome (xerostomia), dry-nose syndrome (xeromycteria), dry-skin syndrome (xeroderma), dry-vagina syndrome (symptom of vaginal dryness); chronic pancreatitis, chronic gastritis, and chronic bronchitis due to the depression of external secretion. Especially, those with conditions which are likely to induce dry-eye syndrome include hypolacrimation, alacrima, xerophtalmia, Sjxc3x6gren""s syndrome, dry keratoconjunctivitis, Stevens-Johnson syndrome, ocular pemphigoid, marginal blepharitis, diabetes, post cataract operation and allergic conjunctivitis. In addition, those with dry-eye syndrome, which may be induced by aging, long term VDT operation, dryness of an air-conditioned room.
Systemic factors which may cause dry-mouth syndrome includes febrile disease, hypohydremia, endcrinopathy (myxedema, Basedow""s disease, diabetes insipidus, etc.), metabolic disorders (diabetes, uremia, liver cirrhosis, etc.), deficiency of vitamin A or B, autoimmune diseases (Sjxc3x6gren""s syndrome, progressive scleroderma, etc.), anemia, bleeding, aging, various medications (sedatives, parasympatholytic drugs, antihistamines, etc.). In addition, topical factors may include sialadenitis, atrophy of salivary gland, sequela of radiotherapy, malformation ecodermal dysplasia, etc) and so forth.
The external secretion disorders means a state where abnormal external secretion (i.e. decrease or stop of the secretion), which may be caused by any etiology, is observed, especially the state with abnormal lacrimal fluid secretion including basal tear secretion, and abnormal salivation.
The method of the present invention may be effectuated by administering a composition comprising a fatty acid derivative as an active ingredient to the subject either orally or parenterally. The dosage form of the composition may be eye drops, ophthalmic ointment, sublingual tablets, troches, chewable tablets, collutoriums, sprays, ointments, powders, granules, tablets, capsules, suppository and vaginal suppository. Dosage forms for topical application, such as eyedrops, ophthalmic ointment, sublingual tablets and ointment are preferable. These dosage forms may be prepared according to any of conventional methods.
The composition used in the present invention may be admixed with an appropriate pharmaceutically acceptable additive. The additive is a compound which may be used together with the unsaturated fatty acid derivative of the invention and may include excipient, diluent, filler, solvent, lubricant, adjuvant, binder disintegrator, coating agent, cupsulating agent, ointment base, suppository base, aerosol base, emulsifier, dispersant, suspensing agent, thickener, isotonic agent, buffering agent, analgesia, preservative, anti oxidant, corrigent, flavor, colorant, and functional agent (for example, cyclodextrin and biodegradable polymer). The additive may be selected based on any of reference books on pharmaceuticals.
The composition used in the present invention may further be admixed with any of pharmaceutically active agents in so far as said agent is compatible with the purpose of the present invention.
In the present invention, the xe2x80x9ceffective amountxe2x80x9d of a fatty acid derivative may vary depending on the kind of the fatty acid used, the condition to be treated, age and body weight of the patient, dosage form, duration of the treatment, desired therapeutic effect and so on. For example, when the composition to be used in the treatment is formulated as eyedrops, a dosage form containing 0.000001-10.0 wt %, preferably 0.00001-1.0 wt % of the fatty acid derivative may be administered several drops per one eye, preferably 1-4 drops, several times per day, preferably, 1-6 times per day. When it is formulated as a sublingual tablet, a dosage form containing 0.000001-10.0 wt %, preferably 0.00001-1.0 wt % of the fatty acid derivative may be administered in the oral cavity several times, preferably 1-6 times per day. Further, when it is formulated as an ointment, topical administration of a dosage form containing 0.000001-10.0 wt %, preferably 0.00001-1.0 wt % of the fatty acid derivative for several times, preferably, 1-6 times per day may provide an enough effect.